PEMbrolizumab Plus Lenvatinib In Second Line And Third Line Malignant Pleural MEsotheLiomA Patients: A Single Arm Phase II Study (PEMMELA).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Feb 2021 → ongoing

Decision date (initial)

2024-09-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme (MSD)

External identifiers

EU CT number

2024-516618-39-00

EudraCT number

2019-002560-28

ClinicalTrials.gov

NCT04287829

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To determine the objective response rate (ORR), defined by Modified RECIST 1.1 criteria for pleural mesothelioma, of the combination of pembrolizumab - lenvatinib in pre-treated patients with MPM

Secondary objectives 3

1. To describe the safety of pembrolizumab- lenvatinib in patients with MPM.
2. To describe the disease control rate (DCR) at 3 and 6 months, clinical benefit, progression free survival (PFS), overall survival (OS) and duration of response (DOR)
3. To describe ORR and PFS by independent radiological review

Conditions and MedDRA coding

malignant pleural mesothelioma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Histologically or cytologically diagnosed malignant pleural mesothelioma, age at least 18 years
2. Progressive disease after at least 1 and maximal 2 prior systemic treatment lines: - Cohort 1: patients in which one of the lines contains a platinum-based doublet (both cisplatin and carboplatin are allowed) for unresectable MPM - Cohort 2: patients with only nivolumab-ipilimumab immunotherapy as first line treatment for unresectable MPM. No prior chemotherapy.
3. Measurable disease. At least one measurable lesion according to Modified RECIST 1.1 for pleural mesothelioma. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
4. WHO-ECOG performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to date of allocation
5. Adequate organ function, including : Hematological Hematologisch o Absolute neutrophil count ≥ 1.5 x 109/l o Platelets≥ 150 x 109/l o Hemoglobin ≥6,0 mmol/l (9.0g/dL) Hepatic o Total serum bilirubin ≤ 1.5 times within the upper limits of normal (ULN) (except for Gilbert disease) o ASAT and ALAT < 2.5x ULN o AP (alkaline phosphatases) < 5x ULN (unless bone metastases are present in the absence of any liver disease). Renal o Proteinuria ≤ Grade 2 NCI CTCAE 5.0. Subjects having >1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subject with urine protein ≥1 g/24-hour will be ineligible. o Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥ 40mL/min Coagulation o INR ≤ 1.5 x ULN unless patients is receiving anticoagulant therapy as long as INR is within therapeutic range of intended use of anticoagulants
6. Ability to understand the study and give signed informed consent (or legally acceptable representative if applicable) prior to beginning of protocol specific procedures including the approval of the thoracoscopy or transthoracic pleural biopsy before the first treatment cycle and an optional biopsy before the third treatment cycle
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at screening and no change in hypertensive medication within 1 week before the cycle 1/day1.
8. A female is eligible if she is not pregnant and not breastfeeding (see 4.3.1.2. Age and reproductive status) (contraceptive methods appendix G)
9. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception to avoid pregnancy during treatment and for 120 days a
10. A male participant who agrees to use contraception as detailed in age and reproductive status breastfeeding (see 4.3.1.2 Age and reproductive status) (contraceptive methods appendix G)
11. Anticipated life expectancy of ≥3 months

Exclusion criteria 17

1. Presence of clinically relevant treatment-related toxicity from previous chemotherapy, targeted therapy and/or radiotherapy. Note: Participates must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤2 neuropathy may be eligible
2. Active uncontrolled infection, severe cardiac dysfunction (i.e. unstable angina, history of myocardial infarction within the past 12 months prior to screening, congestive heart failure > NYHA II, serious cardiac arrhythmia), unstable peptic ulcer, unstable diabetes mellitus or other seriously disabling condition
3. Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with another agent agents direct to another stimulatory or co-inhibitory T-cell receptor (eg CTLA-4, OC-40, CD137) or TKI or antibody targeting angiogenesis in the first cohort. Patients who have been treated with autologous tumor cell vaccination (eg. Dendritic cell-based immunotherapy) will be eligible.
4. Concomitant administration to any other experimental drugs under investigation ≤ 4 weeks prior to first admission of pembrolizumab- lenvatinib
5. Prior radiotherapy within 2 weeks before start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids as therapy for radiation induced toxicities. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
6. Major injuries and/or surgery within the past 4 weeks prior to first study dose with incomplete wound healing
7. History of clinically significant hemorrhagic or thromboembolic event within 6 months of screening
8. Known inherited predisposition to bleeding or thrombosis
9. Live vaccine within 4 weeks prior to the first dose of study drug
10. Symptomatic and/or hemorrhagic brain metastases
11. Known hypersensitivity to trial drug or their excipients
12. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. Hormone replacement like eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc. are permitted. Inhaled or topical steroids are not considered a form of systemic treatment.
13. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
14. History of (non-infectious) pneumonitis that required steroids and no current pneumonitis
15. Known history of Human Immunodeficiency Virus (HIV) and/or known history of active TB (Bacillus Tuberculosis) and/or kwon history of hepatitis B or known active Hepatitis C virus
16. Known other malignancy that is progressing or has required active treatment during the previous two years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
17. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The proportion of patients with an objective response, defined by Modified RECIST 1.1 criteria for malignant pleural mesothelioma (see appendix C), determined by the local physician and compare ORR with historical controls.

Secondary endpoints 3

1. Extent of exposure, AEs, SAEs, treatment related AEs (TRAEs/SAEs) , AE’s leading to discontinuation of study drug(s)/withdrawal, fatal TRAEs and deaths. Other AEs that the investigator deemed important to report and reasons for discontinuation of study drug(s). AE grading will be performed by NCI Common Terminology Criteria for Adverse Events Version 5.0.
2. To estimate the disease control rate (DCR) progression-free survival (PFS) determined by defined by ModifiedRECIST 1.1 criteria for malignant pleural mesothelioma Duration of response (DOR) (all determined by the local physician) and overall survival (OS).
3. To describe the DCR, ORR, DOR and PFS by independent radiological review

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

J. A. Burgers

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

J. A. Burgers

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications